1. Field of the Invention
The present invention relates generally to the field of orthopedics. More particularly, it concerns compositions and methods for preparing intraarticular formulations comprising biocompatible pharmaceutical agents and use thereof in treatment of diseases, such as degenerative bone diseases, including osteoarthritis of the knee, hip, or other joints, and similar chronic or acute destructive arthropathies resulting from (auto-)immune disorders or infectious disease.
2. Description of Related Art
Destructive arthropathies of the large joints resulting from inflammatory processes, such as rheumatoid arthritis or sepsis, have various effective medical treatments, such as methotrexate, corticosteroids, non-steroidal anti-inflammatory agents, or in the case of sepsis, antimicrobial therapies. However, in osteoarthritis or similar chronic joint diseases, even when inflammatory damage has been adequately treated, mechanical dysfunction persists. In osteoarthritis, a non-inflammatory chronic disease, available medical treatments are relatively limited and are generally restricted to pain control, corticosteroid injection, hyaluronic acid injection, and ultimately joint replacement surgery. In these settings analgesics and corticosteroids provide palliation of symptoms, but disease activity and joint destruction invariably progress due to continued mechanical stress. Indeed, mechanical stress provides one experimental means of creating osteoarthritis in animal models (Langenskiold et al., 1979; Cledes et al., 2006; Pape and Madry, 2013). In patients with significant large joint dysfunction, surgical intervention has become the dominant treatment (Losina et al., 2009). Surgery provides excellent relief but with significant rates of both near-term and long-term complications. For example, total knee replacement (TKR) and total hip replacement (THR) surgeries have a major complication rate of approximately 2%, consisting mostly of infection but including heart attack, stroke, and pulmonary embolism (NIH Consensus Development Conference on Total Knee Replacement, 2003; Minnesota Community Measurement, 2010). Further, there is a need for revision surgery in 1% of TKR cases each year post initial surgery. The rate of revision for THR is 14% (NIH Consensus Development Conference on Total Knee Replacement, 2003). Since osteoarthritis progresses with age, older patients typically have the highest morbidity and are also the least likely to be considered suitable surgical candidates. Furthermore, the cost of TKR is approximately $30,000. Similarly, hyaluronic acid (HA) products (SYNVISC®, HYALGEN®, ORTHOVISC®, and others) have proven efficacy; however, they have disadvantages in that they are rapidly metabolized, and thus lose efficacy over the course of several months. Furthermore, they cost about $3,000 per injection. In addition, physicians generally recommend TKR or THR only for significantly debilitating joint disease. Yet, even with strong physician recommendations the acceptance rate among patients for TKR is only about 13% of eligible patients per year (NIH Consensus Development Conference on Total Knee Replacement, 2003; American Academy of Orthopedic Surgeons; Christensson et al., 2004; Beringer et al., 2007; Lalani et al., 2008; Hsu et al., 2012; Maradit Kremers et al., 2013). Thus, there is a need for methods to treat the significant untreated population that includes patients who refuse surgery or who are not surgical candidates due to age or for other medical reasons, such as comorbid conditions.